Impact of treatments on the clinical value of immune response in breast cancer: an insilico analysis

Immune response to breast cancer (immunogenicity of breast cancer) has clinical relevance. Further, many studies report that traditional therapies affect immune response. For example, popular microtubule-targeting agents modulate immune cell function preclinically. This thesis investigates whether microtubule-targeting agents impact immune responses to breast cancer and their clinical relevance.Using the FinHER randomized phase III adjuvant trial comparing the microtubule-stabilizing agent Doxcetaxel to the microtubule-destabilizing agent Vinorelbine with FEC as backbone chemotherapy, the thesis explored the effect of microtubule-stabilizing and destabilizing agents on breast cancer immune response and patient survival. FinHER specimens were preserved as FFPE blocks. A pilot study was performed to determine whether gene modules derived from FFPE specimens profiled on Affymetrix arrays are reproducible. Additionally, FFPE expression profiles were analyzed for the reliability of published gene modules. The results of this study revealed 1) the loss of biological signals from FFPE expression profiles and 2) the feasibility of producing reproducible gene modules from FFPE specimens using Affymetrix arrays with FFPE-specific sample preparation protocols. Based on the pilot study results, FinHER FFPE specimens were profiled. Furthermore, published studies with chemotherapy regimen details were extracted from the GEO database and integrated for validation. The integration of published gene expression data from GEO was necessary since well-curated large public datasets like TCGA, METABRIC, and MetaGxBreast do not provide a detailed characterization of the chemotherapy regimen needed for validation. Using the FinHER and the integrated GEO datasets, the thesis demonstrated a potential interaction between microtubule targeting agents and immune response to clinical outcomes in adjuvant and neoadjuvant breast cancer settings. This interaction’s clinical relevance is discussed.In conclusion, the thesis demonstrates the potential impact of microtubule agents on the host immune response and its clinical relevance in breast cancer.Doctorat en Sciences biomédicales et pharmaceutiques (Médecine)info:eu-repo/semantics/nonPublishe

Anticonvulsant effect of cytoskeletal depolymerizers in combination with potassium channel opener and adenylate cyclase activator; a causative link with nerve growth factor?

425-430<span style="font-size: 14.0pt;mso-bidi-font-size:9.0pt;font-family:" times="" new="" roman","serif""="">Anticonvulsant effect of cytoskeletal depolymerizing drugs in combination with potassium channel <span style="font-size:13.0pt;mso-bidi-font-size:8.0pt; font-family:" times="" new="" roman","serif""="">(KATP) opener and adenylate cyclase activator was evaluated in animal models of epilepsy. Seizures were induced in the animals by subjecting them to maximal electroshock (MES) or by injecting a chemical convulsant, pentylenetetrazole (PTZ). Moreover a correlation with the nerve growth factor (NGF) was also investigated. The anticonvulsant effect of minoxidil <span style="font-size:13.0pt; mso-bidi-font-size:8.0pt;font-family:" arial","sans-serif""="">(1200µg/kg <span style="font-size: 14.0pt;mso-bidi-font-size:9.0pt;font-family:" times="" new="" roman","serif""="">i.p) and Deacetylforskolin (600 µg/kg i.p) was significantly enhanced in the mice pre-treated with cytoskeletal depolymerizing drugs. On the other hand nerve growth factor potentiated the convulsive phenomenon and decreased the seizure threshold in both the electroshock and chemically induced convulsions. Another interesting feature was the interaction of cytochalasin B, a microfilament disrupter in preventing the action of mNGF and <span style="font-size: 13.0pt;mso-bidi-font-size:8.0pt;font-family:" times="" new="" roman","serif""="">PTZ. This study demonstrates the importance of interaction between cytoskeletal structures and signaling molecules in determining the convulsive threshold. This study clearly points to the importance of the nerve growth factor in convulsive phenomenon. </span

Causes of DMARD withdrawal following ADR within 6 months of initiation among Indian rheumatoid arthritis patients

The present study was conducted in Indian rheumatoid arthritis (RA) patients prescribed disease-modifying anti-rheumatic drugs (DMARDs) to determine the incidence and type of adverse drug reactions (ADRs) leading to their withdrawal in the initial 6 months of therapy. This was considered important as pharmacogenetic variations in the pattern of RA in different populations and genetic differences in efficacy and safety to drugs demand separate studies to be conducted in different populations. Hospital records were used to identify 1,000 consecutive patients with RA fulfilling the American College of Rheumatology criteria and having at least 6-month follow-up. Age, gender, duration of arthritis, drug usage and ADR-related drug withdrawal were recorded from the charts. Most of the patients were put on single DMARD. Combined use of DMARD was less frequent and non-use of DMARD was common; however, disease control was good. The commonest DMARD used in our hospital was hydroxychloroquine 444 (44%) and the commonest combination used was methotrexate with hydroxychloroquine by 55 (6%). Sulphasalazine use showed preference to young and males. Supportive drugs used were NSAIDs by 883 (88%), corticosteroids by 646 (65%), paracetamol by 594 (59%) and amitriptyline by 88 (9%). Incidence of ADR-related DMARD withdrawal was maximum with leflunomide 2/15 (13.33%) followed by methotrexate 9/116 (7.76%), sulphasalazine 6/185 (3.24%), chloroquine 3/131 (2.29%) and hydroxychloroquine 8/444 (1.8%). Severity and symptomatology of disease, genetic pattern of patients, financial status, previous experience of the clinicians and patients, availability of drugs, patient expectations and compliance were the main factors that lead to a difference in pattern of therapy in our patients compared to other population

Effect of potassium channel modulators on toxicity of <i>Cleistanthus collinus</i>

81-85The study was conducted to determine the effects of boiled extract of Cleistanthus collinus on rats by observing ECG changes and electrolyte levels in serum and urine. Influence of minoxidil and glibenclamide on Cleistanthus collinus induced toxicity was determined. ED50 for arrhythmia, changes in contractility and heart rate were recorded using the isolated frog heart. Cleistanthus at low doses caused transient tachycardia and increase in contractility and at high dose caused arrhythmia and cardiac arrest in rat. LD50 was found to be 1690 mg/kg. Minoxidil potentiated cardiac toxicity, whereas glibenclamide did not produce any significant change. High concentration of potassium in Cleistanthus extract hindered comparison of its levels. There was excretion of sodium even in the presence of hyponatraemia. Cleistanthus at low dose caused transient tachycardia and increase in contractility and at high dose caused arrhythmia and cardiac arrest in isolated frog heart. ED50 for arrhythmia was found to be 1406 mg/kg. Acute toxicity was mainly due to depressive cardiac activity of Cleistanthus. It also caused renal failure. Potassium channel modulators did not have important role in acute cardiac toxicity treatment. Probably in chronic toxicity, electrolyte level changes are involved and potassium channel modulators might have a role

Feasibility of developing reliable gene expression modules from FFPE derived RNA profiled on Affymetrix arrays

The reliability of differential gene expression analysis on formalin-fixed, paraffin-embedded (FFPE) expression profiles generated using Affymetrix arrays is questionable, due to the high range of percent-present values reported in studies which profiled FFPE samples using this technology. Moreover, the validity of gene-modules derived from external datasets in FFPE microarray expression profiles is unknown. By generating matched gene expression profiles using RNAs derived from fresh-frozen (FF) and FFPE preserved breast tumors with Affymetrix arrays and FF/FFPE RNA specific amplification-and-labeling kits, the reliability of differential expression analysis and the validity of gene modules derived from external datasets were investigated. Specifically, the reliability of differential expression analysis was investigated by developing de-novo ER/HER2 pathway gene-modules from the matched datasets and validating them on external FF/FFPE gene expression datasets using ROC analysis. Spearman’s rank correlation coefficient of module scores between matched FFPE/frozen datasets was used to measure the reliability of gene-modules derived from external datasets in FFPE expression profiles. Independent of the array/amplification-kit/sample preservation method used, de-novo ER/HER2 gene-modules derived from all matched datasets showed similar prediction performance in the independent validation (AUC range in FFPE dataset; ER: 0.93–0.95, HER2: 0.85–0.91), except for the de-novo ER/HER2 gene-module derived from the FFPE dataset using the 3’IVT kit (AUC range in FFPE dataset; ER: 0.79–0.81, HER2: 0.78). Among the external gene modules considered, roughly ~50% gene modules showed high concordance between expression profiles derived from matching FF and FFPE RNA. The remaining discordant gene modules between FF and FFPE expression profiles showed high concordance within matching FF datasets and within matching FFPE datasets independently, implying that microarrays still require improved amplification-and-sample-preparation protocols for deriving 100% concordant expression profiles from matching FF and FFPE RNA.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Impact of Insulin Tregopil and Its Permeation Enhancer on Pharmacokinetics of Metformin in Healthy Volunteers: Randomized, Open‐Label, Placebo‐Controlled, Crossover Study

Oral insulin tregopil (IN‐105; a new drug under development) may be coadministered with oral antidiabetic drugs, such as metformin in patients with type 2 diabetes mellitus for optimal glycemic control. IN‐105 has sodium caprate excipient, a permeation enhancer, for enhancing absorption in the stomach and increasing bioavailability via an oral route. Sodium caprate may increase bioavailability of metformin by a similar mechanism. Therefore, it was necessary to study the effect of IN‐105 on pharmacokinetics (PKs) of metformin. In this randomized, open‐label, cross‐over study, metformin was administered to healthy volunteers receiving IN‐105/placebo under fed/fasting conditions. The 90% confidence interval (CI) of the geometric mean ratio of the area under the curve from time zero to infinity (AUC0‐inf; fasting and fed) and peak plasma concentration (Cmax; fed) of metformin were within 0.80–1.25 acceptance range. Under fasting conditions, the upper bound margin of Cmax was just beyond this range (i.e., 1.27) and was concluded as functionally not relevant. There was no clinically significant effect of sodium caprate/IN‐105 on PKs of metformin under fasting/fed conditions, and it was safe

Plastic waste to liquid fuel: A review of technologies, applications, and challenges

One of the most promising approaches for converting waste plastics into oil is fast pyrolysis. This study reviews the current state of the art and recent progress made on the thermal conversion of plastic to oil technologies, and their uses as alternatives to fossil fuels. The fuel properties of waste plastic pyrolysis oil (WPPO) are close to the diesel fuel. The WPPO produced from high-density polyethylene, low-density polyethylene, polypropylene, and polystyrene have higher heating values ranging from 40 to 43 MJ/kg. The thermal efficiency of neat WPPO (or blends) was slightly lower than diesel or gasoline. The WPPO has a shorter ignition delay than diesel due to its high cetane number. The WPPO fuels have a lower peak in-cylinder pressure and heat release rate than diesel. Engine-out emissions such as smoke, CO, and CO 2, are lower than diesel. The NO x emissions are higher than diesel, which can be reduced with exhaust gas recirculation or use of additives. Our study reveals that the WPPO is a promising alternative fuel for diesel engine applications